{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T06:50:12Z","timestamp":1790232612973,"version":"4.1.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2025,9,9]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\u03b2-Adrenergic receptors (\u03b2ARs) are prototypical G protein\u2013coupled receptors that regulate contractility in the normal heart and pathological remodeling in disease. Canonical \u03b2AR signaling originates at the plasma membrane, but functional \u03b2ARs have been localized to intracellular membranes such as the endosome, sarcoplasmic reticulum, Golgi, and nuclear envelope. The functional significance of these intracellular receptors remains unclear, including whether they regulate cellular processes distinct from those regulated by plasma membrane receptors and whether they can be independently targeted for therapeutic benefit.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>Live cell imaging of rat and human cardiomyocytes expressing novel compartment-specific modulators of \u03b2AR activity and fluorescent biosensors was used to study the compartment-specific \u03b2AR regulation of second messengers and to target enzyme activity. Compartmentalized signaling was compared with myocyte gene expression and hypertrophy. Adeno-associated virus gene delivery conferring gain and loss of perinuclear \u03b2AR activity was studied in wild-type mice and a mouse model of familial dilated cardiomyopathy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      We demonstrate here that intracellular \u03b2\n                      <jats:sub>1<\/jats:sub>\n                      ARs present on Golgi membrane facing the outer nuclear membrane regulate a perinuclear cAMP compartment containing the A-kinase anchoring protein 6\u03b2 signalosome, conferring selective regulation of perinuclear cAMP-dependent protein kinase activity independently of \u03b2ARs at the plasma membrane or endosome. The A-kinase anchoring protein 6\u03b2 compartment is shown to be of nanometer scale and dependent on local restriction of cAMP diffusion. In addition, perinuclear \u03b2ARs are shown to be sufficient and necessary for activation of the Ca\n                      <jats:sup>2+<\/jats:sup>\n                      -dependent calcineurin\u2013nuclear factor of activated T cells pathway and myocyte hypertrophy in vitro. Accordingly, adeno-associated virus 9\u2013based delivery of an outer nuclear membrane\u2013localized pepducin, which selectively activated perinuclear \u03b2ARs in vitro, induced dilated cardiomyopathy in wild-type mice. Conversely, in vivo delivery of an outer nuclear membrane\u2013localized nanobody, which selectively inhibited perinuclear \u03b2ARs in vitro, improved cardiac function and inhibited pathological remodeling in a mouse model of familial dilated cardiomyopathy with established disease.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      These results demonstrate that \u03b2\n                      <jats:sub>1<\/jats:sub>\n                      ARs localized to Golgi membranes facing the outer nuclear membrane regulate A-kinase anchoring protein 6\u03b2 signalosomes required for the induction of pathological cardiac remodeling, defining an intracellular nanocompartment. Proof of concept is provided for a novel therapeutic approach for familial dilated cardiomyopathy, with potential application to other forms of cardiovascular disease.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.124.072682","type":"journal-article","created":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T09:00:15Z","timestamp":1752656415000},"page":"682-698","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":9,"title":["Unique Role of Intracellular Perinuclear \u03b2\n                    <sub>1<\/sub>\n                    -Adrenergic Receptors in Defining Signaling Compartmentation and Pathological Cardiac Remodeling"],"prefix":"10.1161","volume":"152","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4622-2720","authenticated-orcid":true,"given":"Moriah Gildart","family":"Turcotte","sequence":"first","affiliation":[{"name":"Calhoun Center for Cardiology, University of Connecticut Health Center, Farmington (M.G.T., S.M.P., K.L.D.-K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Maj","family":"Samuelsson","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology and Medicine, Stanford Cardiovascular Institute, Stanford University, Palo Alto, CA (A.-M.S., J.L., Z Q., M.S.K.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3999-5583","authenticated-orcid":true,"given":"Sofia M.","family":"Possidento","sequence":"additional","affiliation":[{"name":"Calhoun Center for Cardiology, University of Connecticut Health Center, Farmington (M.G.T., S.M.P., K.L.D.-K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3018-0570","authenticated-orcid":true,"given":"Jinliang","family":"Li","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology and Medicine, Stanford Cardiovascular Institute, Stanford University, Palo Alto, CA (A.-M.S., J.L., Z Q., M.S.K.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuyun","family":"Qin","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology and Medicine, Stanford Cardiovascular Institute, Stanford University, Palo Alto, CA (A.-M.S., J.L., Z Q., M.S.K.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7005-6953","authenticated-orcid":true,"given":"Michael S.","family":"Kapiloff","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology and Medicine, Stanford Cardiovascular Institute, Stanford University, Palo Alto, CA (A.-M.S., J.L., Z Q., M.S.K.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0500-5698","authenticated-orcid":true,"given":"Kimberly L.","family":"Dodge-Kafka","sequence":"additional","affiliation":[{"name":"Calhoun Center for Cardiology, University of Connecticut Health Center, 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